Preparation of choline base and choline salts



Unite States Patent C) PREPARATION OF BASE AND CHOLINE Eben G. Blackettand Arnold J. Soliday, Marietta, Ohio, assignors to American CyanamidCompany, New York, N. Y., a corporation of Maine No Drawing. ApplicationJanuary 6, 1955, Serial No. 480,268

7 Claims. (Cl. 260-2515) has increased considerably and these agents nowoccupy an important place both in therapy and as a component along withother vitamins in various dietary supplements. However, because of thenature of choline and its salts it has been diificult to prepare cholineand its salts in the high purities necessary when these products areintended for human consumption. Various physical properties and state ofmatter are also requisite when the products are to be incorporated intopills, capsules and tablets along with other materials. Efiicient andeconomical means of producing choline and its various salts in pure formare, therefore, desirable. and necessary.

The customary procedure for the preparation of choline base involves thepreparation of choline chloride by any of the conventional procedures,and then treating the choline chloride with silver oxide or silverhydroxide to precipitate silver chloride, leaving the choline base whichmay then be converted to choline salts by reaction with a suitable acid.7

In the described procedure, several steps are involved and the use ofcostly solvents is required which is an economic disadvantage sinceanhydrous choline chloride is an expensive starting material.

The present invention is based upon the discovery that when an aqueoussolution of trimethylamine is reacted with ethylene oxide, the resultingaqueous solution of choline base can be used directly to prepare variouscholine salts by neutralization of the choline base with an appropriateacid.

The present invention thereby aifords an economic advantage over thestandard procedures since not only is an aqueous procedure moreeconomical than the anhydrous choline chloride process, but it is notnecessary to go through any steps to isolate the choline base as wasnecessary heretofore, nor are any costly solvents required since wateris the only solvent used.

It has been proposed to prepare tricholine citrate by reactingapproximately stoichiometric amounts of ethylene oxide withtrimethylamine. In this process, the choline base is generallyoverneutralized with citric acid because of the presence of someunreacted trimethylamine. The tricholine citrate thus formed iscontaminated with trimethylamine citrate which is formed as aconsequence of the neutralization of the choline base with citric acid.

In a preferred embodiment of the present invention, we have discoveredthat by the use of a two-step .neutralization procedure in thepreparation of various choline salts, such as, for example, trichlolinecitrate, it is possible to obtain a product which is of a desirablylight color and completely uncontaminated with trimethylamine citrate.

In this aspect of the present invention, the aqueous solids.

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solution of the choline base, prepared as hereinbefore described, ispartially neutralized with, for example, citric acid. The unreactedtrimethylamine is then removed by distillation and the remaining cholinebase is neutralized by adding the required amount of citric acid. The'upper limit of neutralization, namely, about 95%, is fairly criticalsince if somewhat more than 95% neutralization is accomplished,trimethylamine citrate is formed as a side reaction and which remains asa contaminant and which is undesirable when the products are to be usedfor human consumption. The lower limit of neutralization, however, issomewhat less critical. As a practical matter, not less than about 50%neutralization is ordinarily practical since with more free basepresent, the greater is the danger of producing a dark colored product.The preferred neutralization is of the order of -95%.

In the more general aspects of the present invention,

an aqueous solution of the choline base is prepared by reactingapproximately stoichiometric amounts of ethylene oxide with an aqueoussolution of trimethylamine, keeping the temperature below about 30 C. Inpractice, there will still be unreacted trimethylamine and which isremoved by vacuum distillation, since ethylene oxide is so reactive thatvarious side reactions take place and a 5-l5% excess is usually requiredif the trimethylamine is to be completely reacted. In actual practice,the distillation may be stopped before the evaporation is complete,leaving an aqueous solution of choline base at a convenientconcentration of between 10 and 50%. The aqueous solutionmaythen bediluted with water, sufficient to result in a 5-25% solution of thebase, and this solution may then be used to prepare the various salts,either by the partial neutralization steps hereinbefore described if theexcess trimethylamine has not been completely removed by vacuumdistillation, or the various salts may be prepared by a simpleneutralization of the choline base with an appropriate acid. The partialneutralization procedure, however, Will generally produce a bettercolored product which is important with liquid preparations. The cholinebase procedure is usually satisfactory, lhowever,'if the product is tobe isolated as a solid because most ofthe dark color washes out in themother liquor.

While the removal of excess trimethylamine followed by neutralization ofthe choline base constitutes the preferred procedure and is necessarywith liquid preparations, trimethylamine salts of other compounds may beremoved by washing when the products are isolated as In this connection,it is interesting to note that choline base is much more stable if theexcess trimethylamine is not removed. Choline base withouttrimethylamine turns dark in a few days While choline base withtrimethylamine shows little change in color after several monthsstorage.

The choline salts may be isolated by conventional means, as by the useof methanol, anhydrous alcohol, etc., :or by the use of certain mixedsolvents which form the subject matter of the copending application ofWhiston and Smith filed concurrently herewith.

Suitable choline salts may be prepared with both organic and inorganicacids. Examples of inorganic acids are hydrochloric acid, nitric acid,phosphoric acid, sulf-uric acid, and the like; examples of organic acidswhich may be used are acetic, propionic, butyric, stearic, and the like;dibasic acids such as oxalic, malonic, succinic, tartaric, citric,gluconic, and the like, as well as amino acids such as glycine, serine,alanine, glutamic, folic, and the like may be used. In general, any typeof organicacid may be used if it has suificient acidity to form a stablecholine salt.

In certain instances, especially desirable salts are prevolume ofisopropanol to the methanolic solution. All pared by this process forcertain uses, for example, the excellent yield of dicholine mucate isobtained. folic acid salt of choline. Choline folate, being made up ofcholine and folic acid, both of which are thera- EXAMPLE 3 peuticagents, affords a compound useful for combina- 5 M0110 Choline Phosphatetion therapy where the effects of both choline and folic To 1211 partsof a aqueous Solution of Choline acldfi are deslred' furthemqrei thlsSalt affords a base is added 98 parts of phosphoric acid. The aqueous im means IPWPOYQUBE chohm and foil; solution is clarified by activatedcharcoal and concenacid into the vitamin formulations since only onecom- Hated under Vacuum to a viscous mass which is then pound need beadded in place of two. N w dissolved in 316 parts of methanol. An equalvolume The invention will be described in greater detail in ofisopropanol is then added to the methanol solution conjunction with thefollowing specific examples in which and the crystalline Cholinephosphate is then removed by the parts are by weight unless otherwisespecified. filtration A good yield of mono choline Phosphdte EXAMPLEl 15(choline dihydrogen phosphate) is obtained. Methanol or anhydrousalcohol may be used for crystallizing the phosphate, but the yields arenot as good as with the methanol-isopropanol mixture.

Trz'chline citrate To 236 parts of a aqueous trimethylamine solution atC. is added 40 parts of ethylene oxide. The mixture is then stirreduntil the reaction is substantially EXAMPLE 6 complete keeping thetemperature below about 30 C. 23

The concentration of the choline base in the reaction Choline steam:

mixture is then determined potentiometrically and sufiio 302-5 p rts f a0% aqueous Ch IiHe as 0111- ciciit citric acid is added to neutralize95% of the ChO- ion is ed 284 parts of stearic acid. dissolved in 2 linebase present. Unreacted trimethylamine is then Parts Of Inethanol- AfterStirring, the Solution of r moved by distillation at 40-45 C. under apressure of 535 line stearate is given a decolorization treatment withacabout 30-50 mm, Suflicient dditional it i id i tivatcd charcoal andthe clarified solution is then evapothen added to completely neutralizethe choline base, fated under Vacuum t0 a Y- This is POuted 0H t0 whichis present to give tricholine citrate. After treatdry r tr ys and th ndr ed, giving the final St arate With ment with activated charcoal andfiltration at 50 C., the p y characteristics Similar to that Of aSoaptricholine ctirate is isolated by removal of the solvent by W Claim;distillation under reduced pressure, the solution tem- In thePreparation choline Salt wherein an perature being kept below 50 C. Thetricholine citrate aqueous Solution of trimethylamine is reacted With yis formed in excellent yield. It has a desirable light ene oxide t formcholine base. the improvement which color and only traces oftrimethylamine. comprises first partial-1y neutralizing the aqueoussolution EXAMPLE 2 of choline base with an acid, distilling off theunreacted trimethylamine under vacuum and completely neutral- J Cholmebase izing the remaining choline base. To 236 parts of a 25% aqueoustrimethylamine solu- 2. The process according to claim 1 in which theacid tion at 30 C. is added 40 parts of ethylene oxide. The is citricacid. mixture is then stirred until the reaction is substantially 40 3.The process according to claim 1 in which the acid complete, keeping thetemperature below about 30 C. is folic acid. Unreacted trimethylamine isremoved under vacuum at 4. The process according to claim 1 in which theacid about -55 C., leaving the choline base in a 40-45% is mucic acid.aqueous solution. The quality is excellent as only traces 5. The processaccording to claim 1 in which the acid of inorganic salts andtrimethylamine are present. 45 is phosphoric acid.

EXAMPLE 3 Dicholine folate u 1 ?H2OO[OH;IITO2H4OHI N N- O OH: OH: w ooe. s@-t s t O N /O O\ CH:

N O[OH;N-QaHLO on (3113 To 2422 parts of a 10% aqueous choline basesolution 6. The process according to claim 1 in which the acid is added441 parts of folic acid; after clarifying with acis stearic acid.tivated charcoal, the water is removed under vacuum 0 7. The processaccording to claim 1 in which the first resulting in a viscous mass.This is then dissolved in neutralization is from about 85% to 95%. 1530parts of methanol and the resulting solution is drowned into 10 timesits volume of 1,4-dioxane. The R f r es C t in th fil Of this patentcholine folate is removed by filtration, washed with UNITED STATESPATENTS acetone and dried at 60 C. An almost quantitative 2,153,591Roeder Apr. 11, 1939 yield of crystalline dicholine folate is produced.2,666,784 Hopfi et a1 Ian. 19, 17954 FW FOREIGN PATENTS Mame 134,220Switzerland Oct. 1, 1929 To 2422 parts of a 10% aqueous solution ofcholine 379 260 G t B it i Au 25, 1932 base is added 210 arts of mucicacid. The aqueo 515, 92 Germany Dec. 20, 1930 solution is clarified byactivated charcoal and th n evap- 593,258 Germany Feb. 23, 1934 oratedunder vacuum to give a viscous mass. This is partially dissolved in 126parts of methanol. The di- OTHER REFERENCES choline mucate is thenprecipitated by adding an equal Meyer et al.: Ber. Deut. Chem. 54,2274-82 (1921).

1. IN THE PREPARATION OF A CHOLINE SALT WHEREIN AN AQUEOUS SOLUTION OFTRIMETHYLAMINE IS REACTED WITH ETHYLENE OXIDE TO FORM CHOLINE BASE, THEIMPROVEMENT WHICH COMPRISES FIRST PARTIALLY NEUTRALIZING THE AQUEOUSSOLUTION OF CHOLINE BASE WITH AN ACID, DISTILLING OFF THE UNREACTEDTRIMETHYLAMINE UNDER VACUUM, AND COMPLETELY NEUTRALIZING THE REMAININGCHOLINE BASE.